WO2017133057A1

WO2017133057A1 - Pharmaceutical applications of schisandra lignan compound

Info

Publication number: WO2017133057A1
Application number: PCT/CN2016/076314
Authority: WO
Inventors: 黄诚; 季光; 顾明; 范圣洁
Original assignee: 上海中医药大学
Priority date: 2016-02-05
Filing date: 2016-03-14
Publication date: 2017-08-10
Also published as: CN105748463A

Abstract

The present invention relates to the field of medicines, and particularly to a schisandra lignan compound or applications of pharmaceutically acceptable salt, hydrate or a prodrug of thereof in the preparation of an FXR transcriptional activator and in the prevention and treatment of obesity and the like. The schisandra lignan compound is selected from schisandrin A, schisandrin B, schisandrin C, bifendate, schisandrol A, schisandrol B, schisanhenol, negsehisandrin G, Schisanwilsonin I, isokadsuranin, anwulignan, schisantherin E, schisanwilsonene, schisandrone or wulignan A1.

Description

Medical use of Schisandra lignans

Technical field

The invention relates to the field of medicine, in particular to a medical use of a schisandra lignan compound.

Background technique

Studies have shown that obesity, hyperlipidemia and type 2 diabetes are chronic diseases that are associated with lifelong, and patients need to take medication in time to avoid worsening the condition. Nonalcoholic fatty liver disease is one of the most common liver diseases. As the disease progresses, nonalcoholic fatty liver may turn into cirrhosis and liver cancer; at the same time, it is also an independent cause of increased cardiovascular disease morbidity and mortality.

Farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that regulates bile acid metabolism, lipid metabolism, glucose metabolism, liver metabolism, and intestinal bacteria by regulating the expression of a series of genes. Growth, etc., which play an important role in diseases such as cholestatic liver injury, inflammatory liver damage, liver fibrosis, fatty liver, dyslipidemia, and atherosclerosis. Studies have shown that bile acids can increase the rate of metabolism, and FXR activated by bile acids may affect body weight by affecting energy expenditure. Recent studies have found that activation of intestinal FXR can promote intestinal FGF15 expression to alter bile acid components, induce browning of white fat, increase energy expenditure and lose weight (Nature Medicine, 21: 159-165, 2015). Therefore, activation of FXR may become a new treatment for weight loss. Recent studies have also found that FXR, in addition to improving the metabolic balance of bile acids, can also regulate liver lipid metabolism, and is expected to become a drug target for the treatment of fatty liver.

Insulin resistance refers to the decrease in the efficiency of insulin-promoting glucose uptake and utilization for various reasons, and the body's compensatory secretion of excess insulin produces hyperinsulinemia to maintain blood sugar stability. Insulin resistance is easy to cause metabolic syndrome and type 2 diabetes.

Schisandra is rich in volatile components, lignans and organic acids. Among them, the lignans are: schisandrin, schisandrin A, schisandrin B, schisandra chinensis, pentoxide, and deoxy Schisandrin.

Summary of the invention

The object of the present invention is to provide a new use of Schisandra lignan compounds.

A first aspect of the present invention provides a schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for use in the preparation of an FXR transcription activator, wherein the schisandra lignan compound is selected From Schisandra A, Schisandrin B, Schisandra C, Biphenyldicarboxylate, Schizandrol A, Schisandrin B, Schisandrol, Schisandra Schisandra G, Heqing Schisandra, Isoflavone, Muzhi Ning, Anwu Lipoprotein, Schisandrin, schisandrin, schisandrone or pentatonic A1.

A second aspect of the present invention provides a schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for use in the preparation of a medicament for preventing and treating obesity, which is a schisandra lignan The compound is selected from the group consisting of Schisandrin A, Schisandrin B, Schisandra C, Biphenyldicarboxylate, Schizandrol A, Schizandrol B, Schisandrin, Schisandra Schisandra G, Heqing Schisandra, and Isoflavones , pentacene, Schisandra ester, schisandrin, schisandrone or pentatonic A1.

A third aspect of the present invention provides a schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for use in the preparation of a medicament or a health care product for preventing and treating fatty liver, the schisandra chinensis The compound is selected from the group consisting of Schisandrin A, Schisandrin B, Schisandra C, Biphenyldicarboxylate, Schizandrol A, Schizandrol B, Schisandrin, Schisandra Schisandra G, Heqing Schisandra, and Schisandra Schisandra Ning, berberine, Schisandrin, schisandrin, schisandrone or pentatonic A1.

A fourth aspect of the present invention provides a schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof for use in the preparation of a medicament for preventing or treating hyperglycemia, which is a schisandra The compound is selected from the group consisting of Schisandrin A, Schisandrin B, Schisandra C, Biphenyldicarboxylate, Schizandrol A, Schizandrol B, Schisandrin, Schisandra Schisandra G, Heqing Schisandra, and Schisandra Schisandra Ning, berberine, Schisandrin, schisandrin, schisandrone or pentatonic A1.

A fifth aspect of the present invention provides a schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for use in the preparation of a medicament for preventing or treating hyperlipidemia, which is a schisandra The lignans are selected from the group consisting of Schisandrin A, Schisandrin B, Schisandra C, Biphenyldiester, Schizandrol A, Schizandrol B, Schisandrin, Schisandra Schisandra G, Heqing Schisandra, and Schisandra Muzhining, pentaphylline, Schisandrin, schisandrin, schisandrone or pentatin A1.

A sixth aspect of the present invention provides a schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for use in the preparation of a medicament or a health care product for controlling insulin resistance, the schisandra chinensis The compound is selected from the group consisting of Schisandrin A, Schisandrin B, Schisandra C, Biphenyldicarboxylate, Schizandrol A, Schizandrol B, Schisandrin, Schisandra Schisandra G, Heqing Schisandra, and Schisandra Muzhining, pentaphylline, Schisandrin, schisandrin, schisandrone or pentatin A1.

In a preferred embodiment, the Schisandra lignan compound is selected from the group consisting of Schisandrin A, Schisandrin B, Schisandra C, Schisandrin A, Schizandrol B, Schisandrin, Schisandra Schisandra G, Heqing Schisandra Or schisandra chinensis.

The details of various aspects of the invention are described in detail in the following sections. The features, objects, and advantages of the invention will be apparent from the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1 shows the effect of schisandra lignans such as schisandrin A, schisandrin B, bifendate, and pentapeptide on FXR transcriptional activity.

Figure 2 shows the concentration dependence of schisandra A, schisandrin B, Schisandrin, bifendate, and pentapeptide on FXR transcriptional activity.

Figure 3 shows the effects of schisandrin A, schisandrin B, bifendate, and pentapeptide on the body weight of obese C57BL/6 mice induced by high fat diet; in the figure: * indicates that compared with the control group, P < 0.05 .

Figure 4 shows the food intake of mice fed with schisandrin, schisandrin, bifendate, and pentoxide.

Figure 5 shows the effects of schisandrin A, schisandrin B, bifendate, and pentapeptide on visceral fat in obese mice.

Figure 6A-F shows the effects of schisandrin A, schisandrin B, bifendate, and pentapeptide on fat weight in obese mice. A: abdominal white fat content; B: subcutaneous white fat content; C: gonadal white fat content; D: white blood fat content of the heart; E: white fat content of the spleen; F: white fat content of the kidney. In the figure: * indicates that P < 0.05 compared with the control group.

Figure 7A-E shows the effects of schisandrin A, schisandrin B, bifendate, and pentapeptide on the metabolic rate of obese C57BL/6 mice induced by high fat diet. A: carbon dioxide; B: oxygen; C: respiratory exchange rate; D: number of movement steps; E: body temperature. In the figure: * indicates that P < 0.05 compared with the control group.

Figure 8A-B shows the effects of schisandrin A, schisandrin B, bifendate, and pentasin on liver lipid content; A: triglyceride content; B: total cholesterol content. In the figure: * indicates that P < 0.05 compared with the control group.

Figure 9 shows the schisandra A, schisandrin B, biphenyl diester, and pentometin on obese mice The effect of abdominal blood glucose; in the figure: * indicates that compared with the control group, P < 0.05; ** indicates that compared with the control group, P < 0.01.

Figure 10 shows the improvement of glucose tolerance test in obese mice by schisandrin A, schisandrin B, bifendate, and pentapeptide. In the figure: * indicates that compared with the control group, P < 0.05; ** indicates P < 0.01 compared with the control group.

Figure 11 shows the improvement of insulin resistance test in obese mice by schisandrin A, schisandrin B, bifendate, and pentapeptide. In the figure: * indicates that P < 0.05 compared with the control group.

Figure 12 shows the improvement of blood lipids in obese mice by schisandrin A, schisandrin B, bifendate, and pentapeptide; A: Schisandrin A; B: Schisandrin B; C: biphenyl diester; : An pentoxide. In the figure: * indicates that P < 0.05 compared with the control group.

detailed description

The present invention is based on the surprising discovery that Schisandra lignans can block the weight gain of C57BL/6 mice induced by high-fat diets, inhibit the increase of body fat cells, and improve fasting blood glucose and insulin resistance in mice. Abnormal blood lipids, etc. In addition, FXR reporter gene analysis showed that Schisandra lignans can inhibit the transcriptional activity of the FXR gene. It is proved that Schisandra lignans not only have significant therapeutic activity against obesity, but also prevent, improve and/or treat various metabolic diseases such as fatty liver, hyperlipidemia, etc. by selectively inhibiting the transcriptional activity of FXR. The role.

As used herein, the "schisandra lignan compound" includes, but is not limited to, the following compounds:

More preferably, the Schisandra lignan compound is selected from the group consisting of Schisandra A, Schisandrin B, Schisandra C, Schizandrol A, Schizandrol B, Schisandrin, Schisandra Schisandra G, Heqing Schisandra, or different Nanzizizi Muzhi Ning.

The invention also provides corresponding all pharmaceutically acceptable salts, hydrates or prodrugs of the above compounds. These salts may be formed by a positively charged moiety (eg, an amine group) of the compound and a negatively charged (eg, trifluoroacetic acid) having an opposite polarity; or by a negatively charged moiety (eg, a carboxyl group) of the compound Positive charges (eg, sodium, potassium, calcium, magnesium) are formed. The compound may contain a non-aromatic double bond with one or more asymmetric centers. Thus these compounds may exist as racemic mixtures, as individual enantiomers, as individual diastereomers, as mixtures of diastereomers, as cis or trans isomers. All of these isomers are expected. The "prodrug of Schisandra lignan compound" generally refers to a substance which, when administered by an appropriate method, can be converted into at least one of the above-mentioned Schisandra chinensis by metabolic or chemical reaction in a subject. a lipoprotein compound or a salt thereof.

The Schisandra lignan compound of the present invention can be obtained by a conventional method in the art such as alcohol extraction, chromatography, or the like. It can be obtained by extraction from plants such as Schisandra, and can also be purchased commercially or by using commercially available raw materials, and synthesized by a conventional compound synthesis method in the prior art. The compounds of the present invention can be synthesized by one of ordinary skill in the art in accordance with known techniques. The synthesized compound can be further purified by column chromatography, high performance liquid chromatography or crystallization.

Synthetic chemical modification, protective functional group methodology (protection or deprotection) is very useful for the synthesis of compounds, and is well known in the art, such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) are disclosed.

The Schisandra lignan compound of the present invention or a pharmaceutically acceptable salt, hydrate or prodrug thereof can effectively inhibit the transcriptional activity of the FXR gene, and thus the compound of the present invention or a pharmaceutically acceptable salt or hydrate thereof Or prodrugs can be used to prepare FXR gene transcriptional inhibitors or to prevent drugs or health products such as obesity, fatty liver, hyperglycemia, hyperlipidemia and insulin resistance.

The content of the Schisandra lignan compound of the present invention or a pharmaceutically acceptable salt, hydrate or prodrug thereof in the composition or pharmaceutical preparation is, for example, 0.0001 to 50% by weight; preferably 0.001 to 30% by weight; more preferably 0.01- 20wt%.

A therapeutically effective amount of the composition of the present invention is used in an amount between 0.001 and 500 mg/kg body weight per day, and any amount within the above range is an effective amount of the present invention. Preferably, the composition of the invention is used in an amount between 0.005 and 300 mg/kg body weight per day; more preferably, the composition of the invention is used in an amount between 0.01 and 100 mg/kg body weight per day. The "therapeutically effective amount" can be used for single or combination therapy of the relevant disease. Those skilled in the art will appreciate that the amount administered at the time of actual administration may be higher or lower than the above dosage range. The "therapeutically effective amount" and specific treatment regimen for a subject (eg, mammalian-human) can be affected by a number of factors, including the pharmacodynamic activity of the compound or prodrug used, the age, weight, and general condition of the subject being administered. , gender, diet, time of administration, susceptibility to disease, progression of the disease, and judgment of the treating physician. The term "treatment" refers to the administration of a schisandra lignan compound of the present invention to a body (containing obesity, symptoms of obesity, or having a precursor to obesity) to treat, alleviate, slow, alter, cure, affect, and improve A tumor, a symptom of a tumor, or a precursor to a tumor.

The Schisandra lignan compound of the present invention or a pharmaceutically acceptable salt, hydrate or prodrug thereof or a composition thereof or a pharmaceutical preparation thereof can be administered orally, intravenously, intramuscularly, subcutaneously, intranasally, or intrarectally. Dosing. Solid carriers such as: starch, lactose, glycerol phosphate, microcrystalline cellulose, brown sugar and white clay, and liquid carriers such as sterile water, polyethylene glycol, nonionic surfactants and edible oils (such as corn oil, Peanut oil and sesame oil) are suitable for the characteristics of the active ingredient and the particular mode of administration required. Adjuvants commonly used in the preparation of pharmaceutical compositions may also be advantageously included, such as flavoring agents, coloring agents, preservatives, and antioxidants such as vitamin E, vitamin C, BHT, and BHA.

The Schisandra lignan compounds of the present invention can also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds (as free base or pharmaceutically acceptable salts) may also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, polyethylene glycol, and mixtures thereof in oils. These preparations contain preservatives to prevent the growth of microorganisms under normal conditions of storage and use.

The pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders (for the temporary preparation of sterile injectable solutions or dispersions). In all cases, these forms must be sterile and must be fluid to facilitate fluid discharge from the syringe. It must be stable under the conditions of manufacture and storage and must be preserved against the contamination and effects of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, an alcohol, a suitable mixture thereof, and a vegetable oil.

The experimental methods in the following examples which do not specify the specific conditions are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. All percentages, ratios, ratios, or parts are by weight unless otherwise indicated.

Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described may be employed in the methods of the invention. The preferred embodiments and materials described herein are for illustrative purposes only.

The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments, may be arbitrarily combined. All of the features disclosed in this patent specification can be used in combination with any of the compositions, and the various features disclosed in the specification can be substituted for any alternative feature that provides the same, equal or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equal or similar features.

Experimental design and materials

1. Drugs and animals

Eight-week-old C57/BJ6 mice weighed approximately 22-25 g/g. The feeding condition is SPF grade, and the feeding temperature is 22-23 °C. 12 hours and nights alternate. Animal feed was purchased from Research Diet (high fat D12492, low fat D12450B).

The following examples are the active drugs of schisandrin A, schisandrin B, schisandrin, bifendate, pentametin and other schisandra lignans, and the chemical structural formulas thereof are shown in the section "Detailed Embodiments".

2. Experimental equipment

Blood glucose meters and test strips were purchased from Roche.

Mouse Metabolic Cage System (TSE, Germany)

Mouse rectal thermometer (Physitema USA)

3. Animals and grouping

Eight-week-old mice were fed with a diet containing 60% (w/w) fat. The treatment group mixed the drugs into the feed, and the mice were free to eat and drink. A total of 6 weeks of treatment. Mouse body weight and food intake were recorded every other day.

Example 1. Schisandra lignans and biphenyl diester activate FXR transcriptional activity test

When the 293T cells were grown to a density of 50% to 80%, the pCMXGal-mFXR-LBD and MH100×4-TK-Luc plasmids were co-transfected into 293T cells with liposomes, and the specificity of FXR was used after 24 hours of culture. GW4064 (10μM) and Schisandrin A, Schisandrin B, Schisandrin, Pentasin and other schisandra lignans and prodrugs of Schisandrin (1, 3, 6, 12, 25 The cells were treated at a concentration of 50 μM). After 24 h of treatment, the cells were washed twice with PBS. Add 65 μL of lysate to each well, shake for 15 min at a shaker, centrifuge for 5 min at 1000 rpm, take 10 μL of the supernatant lysate, add 20 μL of LAR II solution, mix, measure fluorescence, delay for 2 seconds, and read for 10 seconds. The Renilla fluorescence value was used as an internal reference, and the same experiment was repeated three times, three replicate wells per experiment, and statistical data.

Reported gene test, Schisandra A, Schisandra B, Schisandra C, Schisandrin B, Schisandrin, Schizandrol A, Schisandrin, Schisandra, Schisandrin, Heqing Schisandra, Schisandra Glucosamine G, The pentatin A1 and the schisandra chinensis var. chinensis can significantly activate FXR transcriptional activity (see Figure 1 for details). Schisandra A, Schisandrin B, Schisandra C, Biphenyl Diester, Pentasin to FXR Activation of transcriptional activity is concentration dependent (see Figure 2 for details).

Example 2. Effect of schisandrin A, schisandrin B, bifendate, and pentasaponin on body weight of obese mice

After C57BJ/6 mice were fed for 3 months with high-fat diet (Research Diet, D12492), obese mice were mixed with various drugs according to the mass fraction (dosage concentration 0.15wt%) for 6 weeks, every other day. Mouse body weight and food intake were recorded.

Figure 3 shows the effects of schisandrin A, schisandrin B, bifendate, and pentapeptide on the body weight of obese C57BL/6 mice induced by high fat diet; *: indicates that compared with the control group, P < 0.05 . It can be seen from Fig. 3 that the body weight of each group was significantly lower than that of the control group (P<0.05), and Fig. 4 showed that the effect of blocking the weight gain of the mice in each group was not because the drug significantly changed the mice. Daily food intake, indicating that Schisandra A, Schisandra B, bifendate, and pentapeptide can reduce the body weight of obese mice, and have a weight loss effect.

Example 3. Effect of schisandrin A, schisandrin B, bifendate, and pentasaponin on the weight of adipose tissue in obese mice

After C57BJ/6 mice were fed for 3 months with high-fat diet (Research Diet, D12492), obese mice were treated with the above-mentioned administration method (administered at a concentration of 0.15 wt%), administered continuously for 6 weeks, and then anesthetized. The whole abdominal cavity and thoracic cavity of each group were observed to observe the fat cell bulk density of each group of mice, and the white fat of the mice were compared with the abdominal cavity, subcutaneous and gonads, heart, spleen and kidney around each group. Observed and weighed as shown in Figures 5 and 6, it can be seen from Figure 5 that the fat cell bulk density of obese mice treated with schisandrin A, schisandrin B, bifendate, and pentapeptide is significantly reduced. 6 showed that each group of drugs can significantly reduce the weight of adipose tissue in the abdominal cavity, subcutaneous, paragonadal, paraventricular, spleen and renal paralysis of obese mice, which further indicates that each group of drugs has a weight-loss effect.

Example 4. Effect of schisandrin A, schisandrin B, bifendate, and pentapeptide on metabolic rate of obese mice

C57BJ/6 mice were fed with high-fat diet (Research Diet, D12492) for 3 months, and obese mice were treated by the above-mentioned administration method (administration concentration: 0.15 wt%), continuous administration for 4 weeks, continuous observation The body temperature of the mice in each of the above groups was measured for 3 days, and the high-fat control mice and the schisandra-rich schisandrin B were further selected to observe the metabolic signs of the metabolic mice. Figures 7A and 7B show that the carbon dioxide exhaled and oxygen consumption of the schisandrin-treated group were significantly higher than that of the high-fat control group. Figure 7C shows that the respiratory exchange rate of the schisandrin treatment group was significantly higher than that of the day or night. The lipid control group, while Figure 7D shows that administration of Schisandrin B did not significantly increase the daily exercise volume of the mice. Figure 7E shows that the test for rectal body temperature in mice administered to each group showed that the body temperature of the schisandra A, schisandrin and pentoxide was significantly elevated in the control group. These data indicate that Schisandrin A, Schisandrin B, Biphenyldicarboxylate, and Pentapeptide can significantly improve the metabolic rate of obese mice, and suggest that the efficacy of weight loss in each group may be mainly through increasing body temperature and increasing glycolipids in the body. The energy expenditure, rather than significantly increasing the amount of exercise in the mouse.

Example 5. Improvement of fatty liver in obese mice by schisandrin A, schisandrin B, bifendate, and pentapeptide

C57BJ/6 mice were fed with high-fat diet (Research Diet, D12492) for 3 months, and the obese mice were subjected to the above-mentioned continuous administration for 6 weeks. The livers of the above groups were homogenized, extracted with chloroform, and chloroform was extracted. After the layer is dried, it is dissolved in isopropyl alcohol, and the content of triglyceride is measured. The detection result is shown in Fig. 8. After treatment with schisandrin A, schisandrin B, biphenyl diester, and pentametin, schisandrin A, Schisandrin B significantly reduced the levels of triglyceride (Figure 8A) and total cholesterol (Figure 8B) in the liver of obese mice (P < 0.05).

In summary, the results show that Schisandra A, Schisandra B, biphenyl diester, and pentoxide can significantly improve the degree of fatty liver in obese mice.

Example 6. Fasting blood glucose test of obese mice by schisandrin A, schisandrin B, biphenyl diester and pentoxide

C57BJ/6 mice were fed with high-fat diet (Research Diet, D12492) for 3 months, and then administered with Schisandra A, Schisandrin B, Biphenyldicarboxylate, and Pentasin (administered at a concentration of 0.1% by weight) The rats were continuously administered for 4 weeks, and fasting blood glucose was measured; the mice were administered at 9 am, and the mice were fasted overnight before measuring blood glucose. Control mice were fed a low fat diet (Research Diet, D12450B).

Figure 9 shows the schisandra A, schisandrin B, biphenyl diester, and pentapeptide on fasting obese mice The effect of blood glucose, as seen in Figure 9, is that the fasting blood glucose of mice fed with high fat diet is significantly higher than that of low fat control mice. However, fasting blood glucose was significantly decreased in mice fed with schisandrin A, schisandrin B, bifendate, and pentoxin for 6 weeks (P<0.05).

Example 7. Glucose tolerance test of obese mice by schisandrin A, schisandrin B, bifendate, and pentapeptide

C57BJ/6 mice were fed with high-fat diet (Research Diet, D12492) for 3 months, and subjected to the above-mentioned continuous administration for 6 weeks for glucose tolerance test; the mice were fasted overnight before blood glucose measurement. Control mice were fed a low fat diet (Research Diet, D12450B).

The mouse glucose tolerance test was performed: the mice were intraperitoneally injected with 1 g/kg body weight glucose, and the tail vein blood glucose values were measured at 0, 15, 30, 60, and 90 min.

Figure 10 shows the improvement of glucose tolerance test in obese mice by schisandrin A, schisandrin B, bifendate, and pentapeptide. It can be seen from Figure 10: Schisandra A, Schisandrin B, Biphenyl In the test of the obese mice fed with ester and pentoxide, the blood glucose at 30, 60 and 90 min was significantly decreased (P<0.05), indicating Schisandrin A and Schisandra B. Inhibition of insulin resistance in obese mice induced by high fat diet can be achieved by bismuth, bifendate and pentoxide.

Example VIII. Insulin tolerance test of schisandrin A, schisandrin B, bifendate, and pentasin in obese mice

C57BJ/6 mice were fed with high-fat diet (Research Diet, D12492) for 3 months, and subjected to the above-mentioned continuous administration for 6 weeks for insulin tolerance test; the mice were fasted overnight before blood glucose measurement. Control mice were fed a low fat diet (Research Diet, D12450B).

The mouse insulin glucose tolerance test was performed: the mice were rested for 3 days, and the insulin was injected at 10 U/kg body weight, and the tail vein blood glucose level was measured at 0, 15, 30, 60, 90, and 120 minutes, respectively.

Figure 11 shows the improvement of insulin resistance test in obese mice by schisandrin A, schisandrin B, bifendate, and pentapeptide. In the figure: * indicates that P < 0.05 compared with the control group. It can be seen from Fig. 11 that the obese mice fed with schisandrin A, schisandrin B, bifendate, and pentoxin were tested at 0, 15, 60, and 120 minutes in two hours after administration. The blood glucose showed a significant decrease (P<0.05), indicating that schisandra A, schisandrin B, biphenyl diester, and pentane can increase the fat induced by high fat diet. Insulin sensitivity in mice significantly improved insulin resistance in obese mice induced by high fat diet.

Example IX. Effect of schisandrin A, schisandrin B, bifendate, and pentapeptide on blood lipid levels in obese mice

C57BJ/6 mice were fed for 3 months via high-fat diet (Research Diet, D12492) and continuously administered for 6 weeks. Control mice were fed a low fat diet (Research Diet, D12450B).

After the mice were fasted for 12 hours, the hearts were bled, allowed to stand for 2 hours, centrifuged at 3000 rpm for 15 min, mouse serum was collected, and triglyceride, cholesterol, high-density lipoprotein and low-density lipoprotein levels were measured by an automatic biochemical analyzer.

The test results are shown in Figure 12. It can be seen from Figure 12 that the total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL-c) and low-density lipoprotein (LDL-c) levels in the high-fat group were higher than those in the low-fat control. Mouse. The mice in the drug-administered group fed with schisandrin A, schisandrin B, bifendate, and pentoxin had a certain decrease in triglyceride, total cholesterol, and low-density lipoprotein. It is indicated that Schisandrin A, Schisandrin B, Biphenyldicarboxylate and Pentapeptide can significantly reduce serum total cholesterol, high density lipoprotein and low density lipoprotein in obese mice.

Aspects of the present invention have been set forth above. However, it is to be understood that the modifications and modifications may be made by those skilled in the art without departing from the spirit and scope of the invention.

Claims

Use of a Schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for preparing an FXR transcription activator selected from the group consisting of Schisandrin A, Schisandrin B, and Schisandra Propionate, biphenyl diester, schisandra alcohol, schisandrol B, schisandrol, schisandra chinensis G, Heqing schisandra chinensis, schisandra chinensis, saponin, schisandra chinensis, schisandrin, Schisandrin or pentatin A1.
A schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for use in the preparation of a medicament for the prevention or treatment of obesity, which is selected from the group consisting of Schisandrin A and Schisandra B , Schisandra propyl, biphenyl diester, schisandra alcohol, schisandrin B, schisandrol, schisandra chinensis G, Heqing Schisandra chinensis, schisandra chinensis, saponin, schisandra chinensis Schizandene, schisandrone or pentatin A1.
A schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for use in the preparation of a medicament for the prevention or treatment of fatty liver, which is selected from the group consisting of Schisandra A and Schisandra B, Schisandra propyl, biphenyl diester, schisandrol A, Schisandrin B, Schisandrin, schisandra chinensis G, Heqing Schisandra chinensis, Isoflavone schisandra chinensis, Pentaphylline, Schisandrin , schisandrin, schisandrone or pentatonic A1.
A schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for use in the preparation of a medicament for the prevention or treatment of hyperglycemia, which is selected from the group consisting of Schisandra A and Schisandra B, Schisandra propyl, biphenyl diester, schisandrol A, Schisandrin B, Schisandrin, schisandra chinensis G, Heqing Schisandra chinensis, Isoflavone schisandra chinensis, Pentaphylline, Schisandrin , schisandrin, schisandrone or pentatonic A1.
A schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for use in the preparation of a medicament for preventing or treating hyperlipidemia, which is selected from the group consisting of schisandrin A , Schisandra B, Schisandra C, Biphenyldicarboxylate, Schizandrol A, Schizandrol B, Schisandrol, Schisandra Schisandra G, Heqing Schisandra, Isoflavone Schisandra, Anzhizhi, Schisandra Ester pentane, schisandrin, schisandrone or pentatonic A1.
A schisandra lignan compound, or a pharmaceutically acceptable salt, hydrate or prodrug thereof, for use in the preparation of a medicament for the prevention or treatment of insulin resistance, which is selected from the group consisting of Schisandra A and Schisandra B, Schisandra propyl, biphenyl diester, schisandrol A, Schisandrin B, Schisandrin, schisandra chinensis G, Heqing Schisandra saponin, Isoflavone schisandra chinensis, Anzhizhi, Wuwei Ester pentane, schisandrin, schisandrone or pentatonic A1.
The use according to any one of claims 1 to 6, wherein the schisandra lignan compound is selected from the group consisting of schisandrin A, schisandrin B, schisandrin, schisandrin, schisandrin, and schisandrin , schisandra chinensis G, Heqing Schisandra sinensis or schisandra chinensis.